Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P42345 (mTOR)
 26,049 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

N-BP, rapamycin and its derivatives have been originally developed respectively as anti-resorptive and anti-fungal agents. In fact, in vitro and in vivo experiments demonstrated that these compounds are multi-functional molecules exerting their effects on tumour cell growth and bone remodelling. The major challenge in treating cancer relates to mutations in key genes such as p53, Rb or proteins affecting caspase signalling carried by many tumour cells. Whether nitrogen containing bisphosphonates (N-BP) are potent bone inhibitors, they also inhibit tumour cell proliferation and increase atypical apoptosis of bone tumour cells regardless of the p53 and Rb status. N-BP may be then considered as effective therapeutic agents in clinical trials of bone tumours. Rapamycin and its derivatives inhibit mTOR dependent mRNA translation both in osteoclasts and tumour cells. Cellular physiological mechanisms regulated by mTOR integrate many environmental parameters including growth factors, hormones, cytokines, amino acids, energy availability and cellular stresses that are coupled with cell cycle progression and cell growth. Rapamycin and its derivatives as well as N-BP must be considered as bi-(multi) functional molecules affecting simultaneously bone and tumour metabolisms. The present survey describes these two molecular families and discusses their therapeutic interests for primary bone tumours and bone metastases.
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PMID:mTOR inhibitors (rapamycin and its derivatives) and nitrogen containing bisphosphonates: bi-functional compounds for the treatment of bone tumours. 1758 50

Bone is a frequent target of lung cancer metastasis, which is associated with significant morbidity and a dismal prognosis. This study analyzed the soluble factors secreted by lung cancer cells, which are responsible for increasing osteoclast differentiation. Addition of recombinant human interleukin-8 (rhIL-8), present in large amounts in A549-conditioned medium (CM) and NCI-H460-CM, mimicked the inductive effect of A549-CM and NCI-H460-CM on osteoclastogenesis. In contrast, depletion of interleukin-8 (IL-8) from A549-CM and NCI-H460-CM decreased the osteoclastogenesis-inductive properties of A549-CM and NCI-H460-CM. Induction of osteoclast differentiation by lung cancer-derived-CM and rhIL-8 was associated with increased phospholipase D (PLD) activation, and the activations of protein kinase C (PKC) alpha/betaII, extracellular signal-regulated kinase (ERK) 1/2 and AKT/the mammalian target of rapamycin (mTOR). Blocking PLD by a specific inhibitor significantly decreased osteoclast formation by inhibiting PKCs activation and subsequently attenuating the phosphorylation of ERK1/2. PLD inhibitor also completely decreased AKT and mTOR phosphorylation, whereas phosphatidylinositol-3-kinase (PI3K) inhibitor only partially decreased mTOR phosphorylation, suggesting that mTOR activation by PLD is through both PI3K/AKT-dependent and PI3K/AKT-independent manner. In addition, blocking AKT and ERK1/2 by a specific inhibitor also suppressed lung cancer-derived-CM and rhIL-8-induced osteoclast differentiation. Moreover, treatment of peripheral blood mononuclear cells with sera from invasive lung cancer patients increased the formation of osteoclasts. Our study suggests that IL-8 or IL-8-mediated PLD/PKC/ERK1/2 or PLD/AKT signaling is an attractive therapeutic target for osteolytic bone metastases in lung cancer patients.
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PMID:Phospholipase D signaling pathway is involved in lung cancer-derived IL-8 increased osteoclastogenesis. 2010 2

Despite recent improvements in therapeutic management of osteosarcoma, ongoing challenges in improving the response to chemotherapy warrants new strategies still needed to improve overall patient survival. In this study, we investigated in vivo the effects of RAD001 (Everolimus), a new orally available mTOR inhibitor, on the growth of human and mouse osteosarcoma cells either alone or in combination with zoledronate (ZOL), an anti-osteoporotic drug used to treat bone metastases. RAD001 inhibited osteosarcoma cell proliferation in a dose- and time-dependent manner with no modification of cell-cycle distribution. Combination with ZOL augmented this inhibition of cell proliferation, decreasing PI3K/mTOR signaling compared with single treatments. Notably, in contrast to RAD001, ZOL downregulated isoprenylated membrane-bound Ras concomitantly with an increase of nonisoprenylated cytosolic Ras in sensitive and resistant osteosarcoma cell lines to both drugs. Moreover, ZOL and RAD001 synergized to decrease Ras isoprenylation and GTP-bound Ras levels. Further, the drug combination reduced tumor development in two murine models of osteoblastic or osteolytic osteosarcoma. We found that ZOL could reverse RAD001 resistance in osteosarcoma, limiting osteosarcoma cell growth in combination with RAD001. Our findings rationalize further study of the applications of mTOR and mevalonate pathway inhibitors that can limit protein prenylation pathways.
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PMID:Zoledronic acid potentiates mTOR inhibition and abolishes the resistance of osteosarcoma cells to RAD001 (Everolimus): pivotal role of the prenylation process. 2097 12

Bone is a common site of metastatic spread in patients with advanced renal cell carcinoma (RCC) occurring in around one-third of patients enrolled in clinical trials evaluating modern systemic therapies for this disease. Until recently, limited systemic therapeutic options were available for advanced RCC. Nowadays, a quiver of agents have demonstrated activity, including compounds targeting the vascular endothelial growth factor (VEGF) axis and those targeting the mammalian target of rapamycin (mTOR). Despite a detailed biological understanding of how these drugs work, their effect on bony metastases is less clear. Data suggesting that bisphosphonates (namely zoledronic acid) benefit patients with bone metastases from advanced RCC was gathered prior to the targeted therapy era; therefore, there is some uncertainty about their role in patients on modern RCC therapies. This review summarizes the current targeted therapies registered for use in advanced RCC and postulates how some of them might affect the behavior of bone metastases. It also explores the data available on the role of bisphosphonates for bone metastases from RCC, describes methods of assessing response to therapy for bone metastases and delineates future expectations for the treatment of bone metastases from advanced RCC.
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PMID:Renal cell carcinoma bone metastases: clinical advances. 2178 28

Therapy of patients with metastatic renal cell carcinoma (mRCC) requires sequential use of several agents with different mechanisms and minimal cross-resistance between the different agents. Tyrosine kinase inhibitors (TKIs) and mammalian target of rapamycin (mTOR) inhibitors prolong progression-free survival (PFS) in patients with mRCC. Re-challenge with TKIs provides clinical benefit after everolimus in patients with mRCC. We report the case of an mRCC patient with lung and bone metastases, treated sequentially with sunitinib, sorafenib and everolimus. The patient had an objective response in reducing bone metastases, but adaptative and concomitant progression in lung metastases during sunitinib re-challenge. Previously, these lung metastases had responded to sunitinib. This intriguing paradox suggests that not only was sunitinib able to target a specific metastatic site during the re-challenge, as seen by the reduction of bone metastases, but it also elicited a more invasive adaptation and progression of lung tumor cells.
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PMID:Sunitinib re-challenge in metastatic renal cell carcinoma treated sequentially with tyrosine kinase inhibitors and everolimus. 2196 70

With the introduction of molecular targeted drugs, the treatment of metastatic renal cell carcinoma has dramatically changed. There are now four approved targeted therapies that work against the vascular endothelial growth factor and the mammalian target of rapamycin pathways. However, a complete response is rarely observed, and a change of drugs is usually needed. On progression after immunotherapy, sorafenib has demonstrated a progression-free survival(PFS)benefit. After the failure of initial vascular endothelial growth factor(VEGF)therapy, everolimus has shown a PFS benefit in clinical trials. Although drugs are changed during disease progression according to the response evaluation criteria in solid tumors(RECIST)criteria in clinical studies, the choice of targeted therapy and the timing of the start of sequential drugs are usually based on physician preference, reimbursement issues, and the toxicity profile. I usually decide when to start sequential therapy based on the growth speed of targeted lesions and metastatic organs. In patients who have a solitary brain metastasis or bone metastases as new lesions, local treatment of the lesions would also be one of the treatment options. Further studies are warranted to establish a criteria for the changing of drugs after disease progression.
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PMID:[Renal cell carcinoma-response criteria of molecular targeted therapy and the timing of sequential drugs in patients with advanced renal cell carcinoma]. 2306 56

Patients with breast cancer face substantial challenges to bone health from bone metastases, as well as from chemotherapy and endocrine therapies that generally elicit disease control at the cost of increased bone turnover. Consequently, maintaining bone health is of critical importance for these patients. Recently reported results from BOLERO-2 showed significant clinical benefits with adding everolimus to exemestane therapy in postmenopausal women with estrogen-receptor-positive breast cancer recurring or progressing despite nonsteroidal aromatase inhibitor therapy. Moreover, exploratory analyses from BOLERO-2 showed that adding everolimus may have beneficial effects on bone turnover and progressive disease in bone in this patient population. These results are supported by preclinical studies in which mTOR inhibition was associated with decreased osteoclast survival and activity. Thus, everolimus therapy may be able to ameliorate the negative effects of estrogen suppression on bone health. This review discusses the effects of mTOR inhibition on bone health during endocrine therapy.
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PMID:Bone effects of mammalian target of rapamycin (mTOR) inhibition with everolimus. 2383 81

Bone metastases are very common in advanced renal cell carcinoma (RCC) and can have a huge impact on quality of life by leading to skeletal-related events (SREs), including pain, pathologic fractures and spinal cord compression with need for surgery or radiotherapy. Because of their osteolytic aspect and biologic behaviour, these SREs are more common in patients with bone metastases from RCC than from other malignancies. As overall survival is increased by new anti-angiogenic drugs like tyrosine kinase inhibitors and mammalian target of rapamycin inhibitors, the incidence of SREs is rising, making the clinical management of bone metastases in RCC ever more important, especially in the more vulnerable elderly patient. In this review we discuss the current advances and future directions in bone-targeted therapies in patients with RCC with a special focus on the elderly population. Recently, two bone-targeted agents have been approved in the prevention of SREs in advanced RCC: zoledronic acid and denosumab. To date, there is no specific data on the use of bisphosphonates or denosumab in the elderly and specific studies in this setting are warranted. We compare the available evidence for the use and implications of both agents in the elderly patient and give general information on safety concerns that could be more important in these patients.
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PMID:Bone-targeted therapies for elderly patients with renal cell carcinoma: current and future directions. 2407 55

In advanced breast cancer, bone metastases occur in 70 % of patients. Managing the devastating pain associated with the disease is difficult. Rapamycin is an immunomodulatory drug that targets the mammalian target of rapamycin pathway. Rapamycin has been shown to decrease osteolysis associated with metastatic breast cancer in pre-clinical models and to reduce pain in inflammatory and neuropathic models. The aim of this study was to evaluate the effectiveness of rapamycin in reducing pain associated with experimental osteolytic metastases. Bone cancer was induced by intra-tibial injections of murine mammary carcinoma cells (4T1) in immunocompetent BALB/c mice and treated intraperitoneally for up to 5 weeks with vehicle, rapamycin or pamidronate (a bisphosphonate currently used to reduce bone loss in bone cancer patients). The control group received intra-tibial injection with saline (sham) and was treated with vehicle intraperitoneally. Cancer-induced osteolysis was observed histologically and radiographically 2-3 weeks following cancer inoculation and gradually increased with time. Measures of evoked nociceptive behaviors including sensitivity to mechanical, thermal, and cold stimuli and spontaneous nociceptive behaviors (limping, guarding) were evaluated. Significant hypersensitivity to sensory stimuli developed in cancer-bearing mice compared to sham 3 weeks following inoculation. Rapamycin decreased or delayed the development of cancer-induced mechanical, heat, and cold hypersensitivity, while pamidronate reduced heat and cold hypersensitivity. Both rapamycin and pamidronate had a partial protective effect on the spontaneous nociceptive behaviors, limping and guarding. Our data suggest that rapamycin may have efficacy in the management of pain associated with metastatic breast cancer.
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PMID:Osteolysis and pain due to experimental bone metastases are improved by treatment with rapamycin. 2432 32

Anticancer agents may trigger reactivation of hepatitis B virus infection ensuing in asymptomatic to severe liver damage. Preemptive administration of antiviral agents such as lamivudine to patients receiving cytotoxic chemotherapy has been shown to inhibit viral replication and prevent such events. No data are available so far concerning the coadministration of antiviral agents and everolimus, an oral mammalian target of rapamycin inhibitor recently approved for the treatment of advanced renal cell carcinoma. We present in this study the first case to our knowledge of a hepatitis B surface antigen-positive patient with metastatic renal cell carcinoma who has been successfully treated with prophylactic lamivudine and everolimus. Long-term depletion of viral replication was obtained along with stabilization of lung and bone metastases. Hepatitis B surface antigen positivity may be found in up to 10% of cancer patients but should not be considered a contraindication to treatment with everolimus.
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PMID:Prevention of Hepatitis B Virus Reactivation With Lamivudine in a Patient With Advanced Renal Cell Carcinoma Treated With Everolimus. 2436 9


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